| Over the last several decades, epidemiologists have witnessed a rapid rise in the prevalence and severity of asthma. While the factors underlying this increase are clearly complex, environmental factors such as ambient particular matter (PM) appear to play a role. Diesel exhaust particles (DEP), a large contributor to vehicle derived PM, has been shown to act as an immunologic adjuvant when given with antigen; however, there is still a lack of understanding as to what component(s) are responsible for these effects and the underlying mechanisms through which they act. In this work, immunotoxic and genomic responses of three chemically distinct DEP samples were assessed in an ovalbumin (OVA) murine mucosal sensitization model. Immunotoxic endpoints in the lung after OVA challenge demonstrated C-DEP/OVA ≈ A-DEP/OVA > N-DEP/OVA with respect to adjuvancy. To elucidate possible mechanisms for these effects, global gene expression changes in the lung were assessed. While all three DEP/OVA treatments induced expression of cytokine and toll-like receptor pathways, only A- and C-DEP/OVA treatments altered expression of apoptosis pathways. In addition, C-DEP/OVA treatment, which induced the greatest TH2 response post-sensitization, altered expression of DNA damage pathways. This comprehensive approach using gene expression analysis to examine changes at a pathway level provides a clearer picture of the events occurring in the lung after DEP exposure in the presence or absence of antigen. This work also explored immune responses in mice acutely exposed to moderate doses of DE in an OVA mucosal sensitization model and identified possible mechanisms using genomics. Mice exposed to DE/OVA induced a mild adjuvant response. Expression analysis demonstrated DE/OVA altered oxidative stress and metabolism pathways. Together these results demonstrate that exposure to even moderate doses of an air pollutant, such as DE, can enhance allergic sensitization through oxidative stress and inflammatory pathways. Overall the results demonstrate all three DEP samples and DE induced adjuvancy, the extent of which was not solely dependent on the extractable organic content, and gene expression analysis was a more sensitive indicator of early signaling events than the classical immunotoxic endpoints. |
